Cerebellar Degenerations

Abstract

Study of neuronal cell loss now requires an appreciation of the mode of cell death. In neurons, several types of cell death have been described based on the morphology of the dying cell (1) such as necrosis, apoptosis, autophagic cell death, and cytoplasmic cell death (see chapter by Clarke). Among the previous types of cell death, apoptosis and necrosis appear to be distinct at both the biochemical and molecular level. Necrosis may be considered “accidental death” and usually involves rapid and massive disruption to cellular homeostasis. Once initiated, necrosis is essentially irreversible and treatment for human disorders involving necrosis must either prevent the insult from occurring, or prevent damage due to secondary effects, e.g., inflammation. Apoptosis, on the other hand, may offer far more opportunity for intervention: apoptosis is an active process involving the coordination of gene cascades over a period of time. Studies on the molecular events of apoptosis have identified gene products that are an absolute requirement for execution of the apoptotic program in certain cell types and in response to a specific initiating stimulus. The pathology of many human disorders appears to involve dysregulation of apoptosis which, in the healthy individual, is tightly controlled during development and in adulthood. Inappropriate apoptosis may lead to neurodegenerative disease, whereas the failure to remove unwanted cells by apoptosis can lead to tumor development. In this chapter, the importance of cell death in cerebellar disorders will be considered, with a particular emphasis on the relevance of apoptosis to neurodegenerative cerebellar disorders. Reference is made to some animal and cell culture models that help to improve our current understanding of physiological and pathological cell death in the human cerebellum.